scholarly journals Antibody Conjugates for Targeted Therapy Against HIV-1 as an Emerging Tool for HIV-1 Cure

2021 ◽  
Vol 12 ◽  
Author(s):  
Jeffrey C. Umotoy ◽  
Steven W. de Taeye
Keyword(s):  
Neutralizing Antibodies ◽  
Viral Infections ◽  
Therapeutic Potential ◽  
Therapeutic Index ◽  
Production Costs ◽  
People Living With Hiv ◽  
Antibody Conjugates ◽  
Number Of Treatment ◽  
Antibody Derivatives ◽  
Hiv 1

Although advances in antiretroviral therapy (ART) have significantly improved the life expectancy of people living with HIV-1 (PLWH) by suppressing HIV-1 replication, a cure for HIV/AIDS remains elusive. Recent findings of the emergence of drug resistance against various ART have resulted in an increased number of treatment failures, thus the development of novel strategies for HIV-1 cure is of immediate need. Antibody-based therapy is a well-established tool in the treatment of various diseases and the engineering of new antibody derivatives is expanding the realms of its application. An antibody-based carrier of anti-HIV-1 molecules, or antibody conjugates (ACs), could address the limitations of current HIV-1 ART by decreasing possible off-target effects, reduce toxicity, increasing the therapeutic index, and lowering production costs. Broadly neutralizing antibodies (bNAbs) with exceptional breadth and potency against HIV-1 are currently being explored to prevent or treat HIV-1 infection in the clinic. Moreover, bNAbs can be engineered to deliver cytotoxic or immune regulating molecules as ACs, further increasing its therapeutic potential for HIV-1 cure. ACs are currently an important component of anticancer treatment with several FDA-approved constructs, however, to date, no ACs are approved to treat viral infections. This review aims to outline the development of AC for HIV-1 cure, examine the variety of carriers and payloads used, and discuss the potential of ACs in the current HIV-1 cure landscape.

scholarly journals Neutralization of Virus Infectivity by Antibodies: Old Problems in New Perspectives

2014 ◽  
Vol 2014 ◽  
pp. 1-24 ◽  
Author(s):  
P. J. Klasse
Keyword(s):  
Cellular Immunity ◽  
Neutralizing Antibodies ◽  
Viral Infections ◽  
Viral Proteins ◽  
Virus Neutralization ◽  
Virus Infectivity ◽  
Viral Pathogens ◽  
Enveloped Viruses ◽  
Vaccine Candidates ◽  
Hiv 1

Neutralizing antibodies (NAbs) can be both sufficient and necessary for protection against viral infections, although they sometimes act in concert with cellular immunity. Successful vaccines against viruses induce NAbs but vaccine candidates against some major viral pathogens, including HIV-1, have failed to induce potent and effective such responses. Theories of how antibodies neutralize virus infectivity have been formulated and experimentally tested since the 1930s; and controversies about the mechanistic and quantitative bases for neutralization have continually arisen. Soluble versions of native oligomeric viral proteins that mimic the functional targets of neutralizing antibodies now allow the measurement of the relevant affinities of NAbs. Thereby the neutralizing occupancies on virions can be estimated and related to the potency of the NAbs. Furthermore, the kinetics and stoichiometry of NAb binding can be compared with neutralizing efficacy. Recently, the fundamental discovery that the intracellular factor TRIM21 determines the degree of neutralization of adenovirus has provided new mechanistic and quantitative insights. Since TRIM21 resides in the cytoplasm, it would not affect the neutralization of enveloped viruses, but its range of activity against naked viruses will be important to uncover. These developments bring together the old problems of virus neutralization—mechanism, stoichiometry, kinetics, and efficacy—from surprising new angles.

scholarly journals Cross-neutralization of SARS-CoV-2 by HIV-1 specific broadly neutralizing antibodies and polyclonal plasma

2020 ◽  
Author(s):  
Nitesh Mishra ◽  
Sanjeev Kumar ◽  
Swarandeep Singh ◽  
Tanu Bansal ◽  
Nishkarsh Jain ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Neutralizing Antibodies ◽  
Viral Infections ◽  
Cross Reactivity ◽  
Type I ◽  
Human Monoclonal Antibodies ◽  
Critical Feature ◽  
Cd4 Binding Site ◽  
Unique Nature ◽  
Hiv 1

AbstractCross-reactive epitopes (CREs) are similar epitopes on viruses that are recognized or neutralized by same antibodies. The S protein of SARS-CoV-2, similar to type I fusion proteins of viruses such as HIV-1 envelope (Env) and influenza hemagglutinin, is heavily glycosylated. Viral Env glycans, though host derived, are distinctly processed and thereby recognized or accommodated during antibody responses. In recent years, highly potent and/or broadly neutralizing human monoclonal antibodies (bnAbs) that are generated in chronic HIV-1 infections have been defined. These bnAbs exhibit atypical features such as extensive somatic hypermutations, long complementary determining region (CDR) lengths, tyrosine sulfation and presence of insertions/deletions, enabling them to effectively neutralize diverse HIV-1 viruses despite extensive variations within the core epitopes they recognize. As some of the HIV-1 bnAbs have evolved to recognize the dense viral glycans and cross-reactive epitopes (CREs), we assessed if these bnAbs cross-react with SARS-CoV-2. Several HIV-1 bnAbs showed cross-reactivity with SARS-CoV-2 while one HIV-1 CD4 binding site bnAb, N6, neutralized SARS-CoV-2. Furthermore, neutralizing plasma antibodies of chronically HIV-1 infected children showed cross neutralizing activity against SARS-CoV-2. Collectively, our observations suggest that human monoclonal antibodies tolerating extensive epitope variability can be leveraged to neutralize pathogens with related antigenic profile.ImportanceIn the current ongoing COVID-19 pandemic, neutralizing antibodies have been shown to be a critical feature of recovered patients. HIV-1 bnAbs recognize extensively diverse cross-reactive epitopes and tolerate diversity within their core epitope. Given the unique nature of HIV-1 bnAbs and their ability to recognize and/or accommodate viral glycans, we reasoned that the glycan shield of SARS-CoV-2 spike protein can be targeted by HIV-1 specific bnAbs. Herein, we showed that HIV-1 specific antibodies cross-react and neutralize SARS-CoV-2. Understanding cross-reactive neutralization epitopes of antibodies generated in divergent viral infections will provide key evidence for engineering so called super-antibodies (antibodies that can potently neutralize diverse pathogens with similar antigenic features). Such cross-reactive antibodies can provide a blueprint upon which synthetic variants can be generated in the face of future pandemics.

scholarly journals A Little Help From the Follicles: Understanding the Germinal Center Response to Human Immunodeficiency Virus 1 Infection and Prophylactic Vaccines

2017 ◽  
Vol 10 ◽  
pp. 117955571769554 ◽  
Author(s):  
Ebony N Gary ◽  
Michele A Kutzler
Keyword(s):  
Human Immunodeficiency Virus ◽  
Germinal Center ◽  
Neutralizing Antibodies ◽  
People Living With Hiv ◽  
Correlates Of Protection ◽  
Immune Correlates ◽  
Global Pandemic ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Human Immunodeficiency Virus 1

Human immunodeficiency virus 1 (HIV-1) is the causative agent of AIDS. There are currently more than 35 million people living with HIV infection worldwide, and more than 2 million new infections occur each year. The global pandemic caused by HIV-1 is the subject of numerous research projects, with the development of a prophylactic vaccine and a therapeutic cure being the ultimate goals. The classic paradigms of vaccinology have proven incapable of producing a viable vaccine due to the complexity of the virus’ replication cycle, its genetic diversity, and a lack of understanding of the immune correlates of protection. Here, we briefly discuss recent vaccine approaches and the immune correlates of protection from HIV-1 infection with a focus on the role of the germinal center as a reservoir of replication-competent virus and its role in the development of broadly neutralizing antibodies in response to vaccination.

scholarly journals Artificial Anti-HIV-1 Immunogen Comprising Epitopes of Broadly Neutralizing Antibodies 2F5, 10E8, and a Peptide Mimic of VRC01 Discontinuous Epitope

Vaccines ◽  
2019 ◽  
Vol 7 (3) ◽  
pp. 83 ◽  
Author(s):  
Andrey P. Rudometov ◽  
Anton N. Chikaev ◽  
Nadezhda B. Rudometova ◽  
Denis V. Antonets ◽  
Alexander A. Lomzov ◽  
...  
Keyword(s):  
B Cell ◽  
Neutralizing Antibodies ◽  
Viral Infections ◽  
T Cell Epitopes ◽  
B Cell Epitopes ◽  
Linear Peptide ◽  
Peptide Mimic ◽  
Antigenic Properties ◽  
Immunogen Design ◽  
Hiv 1

The construction of artificial proteins using conservative B-cell and T-cell epitopes is believed to be a promising approach for a vaccine design against diverse viral infections. This article describes the development of an artificial HIV-1 immunogen using a polyepitope immunogen design strategy. We developed a recombinant protein, referred to as nTBI, that contains epitopes recognized by broadly neutralizing HIV-1 antibodies (bNAbs) combined with Th-epitopes. This is a modified version of a previously designed artificial protein, TBI (T- and B-cell epitopes containing Immunogen), carrying four T- and five B-cell epitopes from HIV-1 Env and Gag proteins. To engineer the nTBI molecule, three B-cell epitopes of the TBI protein were replaced with the epitopes recognized by broadly neutralizing HIV-1 antibodies 10E8, 2F5, and a linear peptide mimic of VRC01 epitope. We showed that immunization of rabbits with the nTBI protein elicited antibodies that recognize HIV-1 proteins and were able to neutralize Env-pseudotyped SF162.LS HIV-1 strain (tier 1). Competition assay revealed that immunization of rabbits with nTBI induced mainly 10E8-like antibodies. Our findings support the use of nTBI protein as an immunogen with predefined favorable antigenic properties.

scholarly journals Targeting Macrophage Dysregulation for Viral Infections: Novel Targets for Immunomodulators

2021 ◽  
Vol 12 ◽  
Author(s):  
Monica D. Reece ◽  
Ruby R. Taylor ◽  
Colin Song ◽  
Christina Gavegnano
Keyword(s):  
Viral Replication ◽  
Disease Progression ◽  
Viral Infections ◽  
Neurological Deficits ◽  
Viral Reservoir ◽  
Special Focus ◽  
People Living With Hiv ◽  
Major Barrier ◽  
Key Driver ◽  
Hiv 1

A major barrier to human immunodeficiency virus (HIV-1) cure is the latent viral reservoir, which persists despite antiretroviral therapy (ART), including across the non-dividing myeloid reservoir which is found systemically in sanctuary sites across tissues and the central nervous system (CNS). Unlike activated CD4+ T cells that undergo rapid cell death during initial infection (due to rapid viral replication kinetics), viral replication kinetics are delayed in non-dividing myeloid cells, resulting in long-lived survival of infected macrophages and macrophage-like cells. Simultaneously, persistent inflammation in macrophages confers immune dysregulation that is a key driver of co-morbidities including cardiovascular disease (CVD) and neurological deficits in people living with HIV-1 (PLWH). Macrophage activation and dysregulation is also a key driver of disease progression across other viral infections including SARS-CoV-2, influenza, and chikungunya viruses, underscoring the interplay between macrophages and disease progression, pathogenesis, and comorbidity in the viral infection setting. This review discusses the role of macrophages in persistence and pathogenesis of HIV-1 and related comorbidities, SARS-CoV-2 and other viruses. A special focus is given to novel immunomodulatory targets for key events driving myeloid cell dysregulation and reservoir maintenance across a diverse array of viral infections.

Broadly Neutralizing Antibodies for HIV Prevention

2020 ◽  
Vol 71 (1) ◽  
pp. 329-346 ◽  
Author(s):  
Shelly T. Karuna ◽  
Lawrence Corey
Keyword(s):  
Neutralizing Antibodies ◽  
Viral Infections ◽  
Therapeutic Potential ◽  
Broadly Neutralizing Antibodies ◽  
Efficacy Trials ◽  
Preclinical Trials ◽  
Favorable Safety ◽  
Hiv Envelope ◽  
Near Future

In the last decade, over a dozen potent broadly neutralizing antibodies (bnAbs) to several HIV envelope protein epitopes have been identified, and their in vitro neutralization profiles have been defined. Many have demonstrated prevention efficacy in preclinical trials and favorable safety and pharmacokinetic profiles in early human clinical trials. The first human prevention efficacy trials using 10 sequential, every-two-month administrations of a single anti-HIV bnAb are anticipated to conclude in 2020. Combinations of complementary bnAbs and multi-specific bnAbs exhibit improved breadth and potency over most individual antibodies and are entering advanced clinical development. Genetic engineering of the Fc regions has markedly improved bnAb half-life, increased mucosal tissue concentrations of antibodies (especially in the genital tract), and enhanced immunomodulatory and Fc effector functionality, all of which improve antibodies' preventative and therapeutic potential. Human-derived monoclonal antibodies are likely to enter the realm of primary care prevention and therapy for viral infections in the near future.

scholarly journals Custommune: a web tool to design personalized and population-targeted vaccine epitopes

2020 ◽  
Author(s):  
Mohammad Tarek ◽  
Mahmoud Elhefnawi ◽  
Juliana Terzi Maricato ◽  
Ricardo Sobhie Diaz ◽  
Iart Luca Shytaj ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Rapid Development ◽  
Therapeutic Vaccine ◽  
Computational Prediction ◽  
Patient Specific ◽  
People Living With Hiv ◽  
Web Tool ◽  
Cell Immunity ◽  
Hiv 1

AbstractComputational prediction of immunogenic epitopes is a promising platform for therapeutic and preventive vaccine design. A potential target for this strategy is human immunodeficiency virus (HIV-1), for which, despite decades of efforts, no vaccine is available. In particular, a therapeutic vaccine devised to eliminate infected cells would represent a key component of cure strategies. HIV peptides designed based on individual viro-immunological data from people living with HIV/AIDS have recently shown able to induce post-therapy viral set point abatement. However, the reproducibility and scalability of this method is curtailed by the errors and arbitrariness associated with manual peptide design as well as by the time-consuming process.We herein introduce Custommune, a user-friendly web tool to design personalized and population-targeted vaccines. When applied to HIV-1, Custommune predicted personalized epitopes using patient specific Human Leukocyte Antigen (HLA) alleles and viral sequences, as well as the expected HLA-peptide binding strength and potential immune escape mutations. Of note, Custommune predictions compared favorably with manually designed peptides administered in a recent phase II clinical trial (NCT02961829).Furthermore, we utilized Custommune to design preventive vaccines targeted for populations highly affected by COVID-19. The results allowed the identification of peptides tailored for each population and predicted to elicit both CD8+ T-cell immunity and neutralizing antibodies against structurally conserved epitopes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Overall, our data describe a new tool for rapid development of personalized or population-based immunotherapy against chronic and acute viral infections.

scholarly journals Therapeutic potential of HIV-1 entry inhibitor peptidomimetics

2021 ◽  
pp. 153537022199087
Author(s):  
Nneka PU Korie ◽  
Kwesi Z Tandoh ◽  
Samuel K Kwofie ◽  
Osbourne Quaye
Keyword(s):  
Highly Active Antiretroviral Therapy ◽  
Neutralizing Antibodies ◽  
Therapeutic Potential ◽  
Economic Cost ◽  
High Specificity ◽  
Health Concern ◽  
Future Research ◽  
Entry Inhibitors ◽  
Cost Of Production ◽  
Hiv 1

Human immunodeficiency virus 1 (HIV-1) infection remains a public health concern globally. Although great strides in the management of HIV-1 have been achieved, current highly active antiretroviral therapy is limited by multidrug resistance, prolonged use-related effects, and inability to purge the HIV-1 latent pool. Even though novel therapeutic options with HIV-1 broadly neutralizing antibodies (bNAbs) are being explored, the scalability of bNAbs is limited by economic cost of production and obligatory requirement for parenteral administration. However, these limitations can be addressed by antibody mimetics/peptidomimetics of HIV-1 bNAbs. In this review we discuss the limitations of HIV-1 bNAbs as HIV-1 entry inhibitors and explore the potential therapeutic use of antibody mimetics/peptidomimetics of HIV-1 entry inhibitors as an alternative for HIV-1 bNAbs. We highlight the reduced cost of production, high specificity, and oral bioavailability of peptidomimetics compared to bNAbs to demonstrate their suitability as candidates for novel HIV-1 therapy and conclude with some perspectives on future research toward HIV-1 novel drug discovery.

Chemokines in Respiratory Viral Infections: Focus on Their Diagnostic and Therapeutic Potential

2011 ◽  
Vol 31 (4) ◽  
pp. 341-356 ◽  
Author(s):  
Virginia Amanatidou ◽  
Apostolos Zaravinos ◽  
Stavros Apostolakis ◽  
Demetrios A. Spandidos
Keyword(s):  
Viral Infections ◽  
Therapeutic Potential ◽  
Respiratory Viral Infections
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